During migration from the blood stream to tissue, immune cells including leukocytes pass through activated endothelial cells to induce immune responses, and many cell adhesion molecules (CAMs), such as integrins, selectins, ICAMs (intracellular adhesion molecule) and VCAMs (vascular cell adhesion molecule), are involved in the adhesion of leukocytes to endothelial cells and their migration to the tissue. Cell adhesion molecules are functionally divided into selectins involved in interaction between leukocytes and endothelial cells, integrins involved in adhesion of leukocytes to endothelial cells, immunoglobulins or the like. These cell adhesion molecules play important roles in many physiological responses such as immune responses, inflammation, and thrombosis.
VCAM-1 is a vascular endothelial cell adhesion molecule, which interacts with integrin (VLA-4) expressed on the surfaces of most leukocytes, excluding neutrophils. VCAM-1 is highly induced on activated endothelial cells by inflammatory signals, and is involved in attachment of leukocytes to the vascular endothelial cells and the subsequent transendothelial migration of leukocytes into the damaged tissues.
Despite lots of publications regarding with the role of VCAM-1 in inflammation and cancer and VLA-4 interaction, the development of a neutralizing antibody to VCAM-1 has not been actively studied. Although M/K-2.7, a monoclonal antibody to mouse VCAM-1, was recently developed and shows an inhibitory effect on joint inflammation in a collagen-induced arthritis mouse model, the antibody is specific only to a mouse model and thus the usefulness of the antibody should be further tested for clinical application.
Further, VCAM-1 consists of seven IgG-like domains and its domains 1 and 4 are substantially involved in binding with the ligand, integrin (α4β1 or α4β7) (1995, PNAS, 92:p 5714; 1995, The journal of immunology, 155: p 3135 et al.). Therefore, in order to inhibit the interaction between a VCAM-1 antigen and its ligand, effective neutralizing antibodies should have a strong affinity to domain 1 or 4. In this regard, there is an urgent need to develop a fully human monoclonal antibody which shows a specific cross-reactivity between mouse and human VCAM-1 for preclinical and clinical study, which effectively inhibits the interaction between VCAM-1 antigen and integrin, and minimizes the risk of immunogenicity.